Nocturnal Sleep Dynamics Alterations in the Early Stages of Behavioral Variant Frontotemporal Dementia.

STUDY OBJECTIVES: Sleep disorders have been recognized as an integral component of the clinical syndrome in several neurodegenerative diseases, including Alzheimer's Disease (AD). However, limited data exists for rarer types of neurodegenerative diseases, such as behavioral variant Frontotemporal Dementia (bvFTD). This study aims to analyze EEG power spectra and sleep stage transitions in bvFTD patients, hypothesizing that bvFTD may show distinctive sleep stage transitions compared to patients with Alzheimer's Disease (AD). METHODS: Eighteen probable bvFTD patients and eighteen age- and sex-matched probable AD patients underwent overnight polysomnography (PSG) and completed sleep disorders questionnaires. Sleep questionnaires, full-night EEG spectra, and sleep stage transitions indexes were compared between groups. RESULTS: bvFTD patients had higher Insomnia Severity Index (ISI) scores (95%CI: 0, 5) and reported poorer sleep quality than AD patients (p<0.01). Compared to AD, bvFTD patients showed higher N1 percentage (95%CI: 0.1, 6), lower N3 percentage (95%CI: -13.6, -0.6), higher sleep-wake transitions (95%CI: 1.49, 8.86) and N1 sleep-wake transitions (95%CI: 0.32, 6.1). EEG spectral analysis revealed higher spectral power in bvFTD compared to AD patients in faster rhythms, especially sigma rhythm, across all sleep stages. In bvFTD patients, sleep-wake transitions were positively associated with ISI. CONCLUSIONS: Patients with bvFTD present higher rates of transitions between wake and sleep than AD patients. The increased frequency of sleep transitions indicates a higher degree of sleep instability in bvFTD, which may reflect an imbalance in sleep-wake promoting systems. Sleep stage transitions analysis may provide novel insights into the sleep alterations of bvFTD patients.

Mapping lower-limbs muscle vulnerability in patients with ALS: The role of upper and lower motor neurons.

BACKGROUND: Several studies have reported disproportionate wasting of the flexor muscles of the lower limbs (LL) compared to the extensors in patients with amyotrophic lateral sclerosis (ALS). However, these studies have involved small sample sizes (n ã€ˆ100), and their findings have been inconsistent. Thus, it remains uncertain whether a distinct pattern of LL muscle weakness is specific to ALS. AIMS: To investigate the muscle weakness pattern in the LL at the knee, ankle, and toes in a large cohort of ALS patients and evaluate the relationship between the pattern of muscle strength and the extent of upper (UMN) and lower (LMN) motoneuron impairment. MATERIAL AND METHODS: The strength of flexor and extensor muscle was evaluated in 1250 legs of newly diagnosed ALS patients at the knee, ankle, and foot toes. UMN and LMN burden were assessed using validated scores. Within-subjects ANOVA considering the type of muscle (flexor/extensor) and anatomical sites (knee/ankle/toes) and mixed-factorial ANOVA were conducted to explore the impact of UMN and LMN impairments on the muscle weakness pattern. RESULTS: Muscle strength showed a significant decline from proximal to distal regions. Indeed both flexor and extensor muscles at the knee outperformed those at the ankle and toes. Within each site, extensor muscles exhibited less strength than flexor, except at the knee. Patients with heightened UMN impairment showed a more marked difference between flexors and extensors within each site, with extensor muscles being more compromised at the ankle and toes. Higher LMN impairment corresponded to a more pronounced weakness in flexor muscles at the ankle and toes compared to those at the knee. CONCLUSIONS: The extensor muscle at the knee and the flexors at the foot and toes displayed relative resistance to ALS disease. UMN impairment amplified the differences between flexor and extensor muscles within each site, while LMN impairment demonstrated a clear distal-to-proximal vulnerability.

Nerve conduction study on the split-hand plus index in Amyotrophic lateral sclerosis: correlations with lower motor neuron impairment.

INTRODUCTION: In the arms of patients with Amyotrophic lateral sclerosis (ALS) two peculiar patterns of dissociated muscular atrophy have been described: the split-hand sign (with predominant atrophy of the lateral aspect of the hand, compared to hypothenar eminence) and the split-hand-plus sign (SHPS), a predominant abductor pollicis brevis (ABP) atrophy with sparing of flexor pollicis longus (FPL). AIMS: In this case-control study, we evaluated the diagnostic utility of a neurophysiological indicator of SHPS and assessed its association with clinical features. METHODS: We prospectively studied 59 incident ALS patients, 61 patients with ALS-mimic disorders (OND) and 61 non-neurological controls (NNCs). ABP and FPL compound muscle action potentials (CMAP) amplitudes were obtained by supramaximal stimulation of median nerve at elbow. Split-hand plus index (SHPI) was calculated according to the formula: APB-CMAP/FPL-CMAP. RESULTS: SHPI was significantly lower in ALS compared to OND patients and NNCs (p < 0.0001). SHPI value < 1 was observed in 2% of NNCs and 9% of OND patients and demonstrated an accuracy of 71% in differentiating ALS from OND and an accuracy of 74% in differentiating ALS from NNC. SHPI was associated with higher LMN score, and higher disease severity as quantified by the ALSFRS-r. CONCLUSION: Our results indicate that SHPI is a reliable indicator to distinguish ALS patients from ONDs and NNCs. SHPI was significantly associated to the degree of lower motor neuron impairment but showed no association with upper motoneuron impairment.

Neurophysiological indices for split phenomena: correlation with age and sex and potential implications in amyotrophic lateral sclerosis.

Background: Split phenomena (SP) are characterized by patterns of differential muscle wasting and atrophy, which are highly prevalent in amyotrophic lateral sclerosis (ALS) patients. Several neurophysiological indicators, including the split-hand index (SHI), split-leg index (SLI), and split-elbow index (SEI), have been proposed to assess SP. Nevertheless, their cutoff values and the impact of age and sex on these measures remain unclear. Methods: We prospectively collected neurophysiological data from 300 healthy adult subjects. The following indices were measured from compound muscle action potentials (CMAPs): SHI [abductor pollicis brevis (APBcmap) x first dorsal interosseous (FDI)cmap/adductor digiti minimi (ADMcmap)], SEI (BICEPScmap/TRICEPScmap), SLI (extensor digit brevis (EDB)cmap/abductor Hallucis (AH)cmap), and the neurophysiological ratios APBcmap /ADMcmap and FDIcmap/ADMcmap. Multiple linear regression analysis was used to investigate the association between age, sex, CMAPs, and neurophysiological indicators. Results: The median SHI was 10.4, with a median APBcmap/ADMcmap ratio of 0.9 and a median FDIcmap/ADMcmap ratio of 1.2. The median SEI was 1.6 (IQR:1.1-2.4) and the median SLI was 0.7 (IQR:0.5-1.0). Negative associations were observed between age, most of the CMAPs, and all the neurophysiological indices, except for SLI. The male subjects exhibited significantly higher CMAP values for the first dorsal interosseous (FDI), biceps, and SHI compared to the female participants. Conclusion: Our findings highlight the importance of age- and sex-adjusted normative data for SP indices, which could enhance their diagnostic accuracy and clinical utility in patients with ALS. The SL index appears to be the most reliable indicator, as it showed no significant association with age or sex.

Deep Learning-based Approach for Brainstem and Ventricular MR Planimetry: Application in Patients with Progressive Supranuclear Palsy.

Purpose To develop a fast and fully automated deep learning (DL)-based method for the MRI planimetric segmentation and measurement of the brainstem and ventricular structures most affected in patients with progressive supranuclear palsy (PSP). Materials and Methods In this retrospective study, T1-weighted MR images in healthy controls (n = 84) were used to train DL models for segmenting the midbrain, pons, middle cerebellar peduncle (MCP), superior cerebellar peduncle (SCP), third ventricle, and frontal horns (FHs). Internal, external, and clinical test datasets (n = 305) were used to assess segmentation model reliability. DL masks from test datasets were used to automatically extract midbrain and pons areas and the width of MCP, SCP, third ventricle, and FHs. Automated measurements were compared with those manually performed by an expert radiologist. Finally, these measures were combined to calculate the midbrain to pons area ratio, MR parkinsonism index (MRPI), and MRPI 2.0, which were used to differentiate patients with PSP (n = 71) from those with Parkinson disease (PD) (n = 129). Results Dice coefficients above 0.85 were found for all brain regions when comparing manual and DL-based segmentations. A strong correlation was observed between automated and manual measurements (Spearman ρ > 0.80, P < .001). DL-based measurements showed excellent performance in differentiating patients with PSP from those with PD, with an area under the receiver operating characteristic curve above 0.92. Conclusion The automated approach successfully segmented and measured the brainstem and ventricular structures. DL-based models may represent a useful approach to support the diagnosis of PSP and potentially other conditions associated with brainstem and ventricular alterations. Keywords: MR Imaging, Brain/Brain Stem, Segmentation, Quantification, Diagnosis, Convolutional Neural Network Supplemental material is available for this article. © RSNA, 2024 See also the commentary by Mohajer in this issue.

A novel mutation in the LRSAM1 gene in a family with early onset autosomal dominant Charcot-Marie-Tooth type 2P.

Charcot-Marie-Tooth disease type 2P (CMT2P; MIM #614436) is a specific type of axonal neuropathy caused by mutations in the LRSAM1 gene, which is a RING-type E3 ubiquitin ligase. CMT2P can be inherited in two ways: as an autosomal dominant or autosomal recessive trait. In this report, we describe the clinical characteristics of a family with axonal sensory-motor neuropathy caused by a new variant of the LSRAM1 gene, which is associated with early-onset autosomal dominant CMT2P.

Sleep and circadian rhythm disruptions in behavioral variant frontotemporal dementia.

INTRODUCTION: Sleep and rest-activity rhythm alterations are common in neurodegenerative diseases. However, their characterization in patients with behavioral variant frontotemporal dementia (bvFTD) has proven elusive. We investigated rest-activity rhythm alterations, sleep disturbances, and their neural correlates in bvFTD. METHODS: Twenty-seven bvFTD patients and 25 healthy controls completed sleep questionnaires and underwent 7 days of actigraphy while concurrently maintaining a sleep diary. Cortical complexity and thickness were calculated from T1-weighted magnetic resonance (MR) images. RESULTS: Compared to controls, bvFTD patients showed longer time in bed (95% confidence interval [CI]: 79.31, 321.83) and total sleep time (95% CI: 24.38, 321.88), lower sleep efficiency (95% CI: -12.58, -95.54), and rest-activity rhythm alterations in the morning and early afternoon. Increased sleep duration was associated with reduced cortical thickness in frontal regions. DISCUSSION: Patients with bvFTD showed longer sleep duration, lower sleep quality, and rest-activity rhythm alterations. Actigraphy could serve as a cost-effective and accessible tool for ecologically monitoring changes in sleep duration in bvFTD patients. HIGHLIGHTS: We assessed sleep and circadian rhythms in behavioral variant frontotemporal dementia (bvFTD) using actigraphy. Patients with bvFTD show increased sleep duration and reduced sleep quality. Patients with bvFTD show rest-activity alterations in the morning and early afternoon. Sleep duration is associated with reduced cortical thickness in frontal regions. These alterations may represent an early sign of neurodegeneration.

Hypothalamus and amyotrophic lateral sclerosis: potential implications in sleep disorders.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects both motor and non-motor functions, including sleep regulation. Emerging evidence suggests that the hypothalamus, a brain region that plays a critical role in sleep-wake regulation, may be involved in the pathogenesis of ALS-related sleep disturbances. In this review, we have summarized results of studies on sleep disorders in ALS published between 2000 and 2023. Thereafter, we examined possible mechanisms by which hypothalamic dysfunctions may contribute to ALS-related sleep disturbances. Achieving a deeper understanding of the relationship between hypothalamic dysfunction and sleep disturbances in ALS can help improve the overall management of ALS and reduce the burden on patients and their families.

A Clinical Scale for Rating the Severity of Bulbar Lower Motor Neuron Dysfunction in Amyotrophic Lateral Sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of upper (UMN) and lower motor neurons (LMN) in four different body regions (bulbar, cervical, thoracic, and lumbosacral). Over the past decades, several clinical scoring systems have been developed to assess the UMN and LMN burden in ALS. However, concerning the bulbar LMN burden, the available scoring systems solely assess the presence/absence of bulbar LMN signs without providing a degree of impairment. Therefore, in this study, we proposed a novel scale to stratify subjects with ALS according to the bulbar LMN involvement and assessed its prognostic value. METHODS: We developed a four-item scale based on the LMN signs according to the El Escorial criteria. Ten raters, specializing in ALS or neurocognitive disorders, retrospectively applied the scale to the first evaluation of 195 patients with ALS. Cohen's kappa (Cohen's k) and an intra-class correlation coefficient (ICC) were used to assess the inter-rater reliability. The Kaplan-Mayer estimator was used to estimate survival distribution according to the bulbar scale scores. RESULTS: The raters showed a substantial to excellent agreement with Cohen's k, ranging from 0.834 to 0.975, with an overall ICC of 0.922 (95% CI = 0.906-0.936). The survival distribution was statistically different across the three bulbar scale scores (χ2(2) = 9.50, p < 0.01). CONCLUSIONS: Our bulbar LMN scale represents a reliable measure of the bulbar LMN signs in ALS. This easy-to-administer clinical scale could provide unique information in phenotyping and predicting survival in ALS.

The impact of upper and lower motor neuron burden on diagnostic certainty, and clinical course of spinal-onset amyotrophic lateral sclerosis: a cluster-based approach.

BACKGROUND: Upper motor neuron (UMN) and lower motor neuron (LMN) involvement represent the core clinical features of amyotrophic lateral sclerosis (ALS). Several studies divided patients into prevalent UMN and LMN impairment phenotypes to investigate the association between motor systems impairments and ALS clinical course. However, this distinction was somehow heterogeneous and significantly affected the comparability across studies. AIMS: This study aimed to investigate whether patients spontaneously segregate based on the extent of UMN and LMN involvement without a-priori categorization and to identify potential clinical and prognostic features of different clusters. METHODS: Eighty-eight consecutive spinal-onset ALS patients were referred to an ALS tertiary center between 2015 and 2022. UMN and LMN burden was assessed with the Penn Upper Motor Neuron scale (PUMNS) and the Devine score, respectively. PUMNS and LMN scores were normalized into 0-1 and analyzed using a two-step cluster analysis and the Euclidean distance measure. The Bayesian Information Criterion was used to determine the cluster number. Demographic and clinical variables were tested for differences among the clusters. RESULTS: Three distinct clusters emerged at cluster analysis. Patients in "cluster-1" showed moderate UMN and severe LMN involvement, corresponding to the typical ALS phenotype. Patients in "cluster-2" showed mild LMN and severe UMN damage, corresponding to a predominant UMN phenotype, while "cluster-3" patients showed mild UMN and moderate LMN damage, corresponding to a predominant LMN phenotype. Patients in "cluster-1" and "cluster-2" showed a higher prevalence of definite ALS than those in "cluster-3" (61% and 46 vs 9%, p < 0.001). "Cluster-1" patients had a lower median ALSFRS-r score compared to both "cluster-2" and 3 patients (27 vs 40 and 35, < 0.001). "Cluster-1" (HR: 8.5; 95% CI 2.1-35.1 and p = 0.003) and 3 (HR: 3.2; 95% CI 1.1-9.1; p = 0.03) were associated with shorter survival than those in "cluster-2". CONCLUSIONS: Spinal-onset ALS can be categorized into three groups according to LMN and UMN burden. The UMN burden is related to higher diagnostic certainty and broader disease spread, while LMN involvement is associated with higher disease severity and shorter survival.

Different patterns of spreading direction and motor neurons involvement in a cohort of limb-onset amyotrophic lateral sclerosis patients from Southern Italy: Potential implication on disease course or progression?

BACKGROUND: Currently, there is a lack of knowledge concerning where the pathological process starts and how the neurodegeneration spreads during the course of amyotrophic lateral sclerosis (ALS). AIMS: This study aims to evaluate the spreading direction of the disease and the corresponding clinical characteristics in a cohort of patients with limb-onset ALS. PATIENTS AND METHODS: Consecutive incident ALS patients referring to an ALS tertiary center from Southern Italy, between 2015 and 2021, were recruited in the study. According to the initial directions of spread, patients were dichotomized into horizontal spreading pattern (HSP) or vertical spreading pattern (VSP) groups. RESULTS: Among 137 newly diagnosed ALS, 87 presented a spinal onset. Ten patients with pure LMN were not included in the study. All cases reported a clear spread direction. The frequency of HSP and VSP spreading was similar overall (47 vs. 30). The prevalence of HSP was higher (74% vs. 50%) in patients with upper limb-onset (UL-ALS), compared to patients with lower limb-onset (LL-ALS; p < .05). Conversely, the occurrence of VSP spread was threefold higher in patients with LL-ALS, compared to UL-ALS (p < .05). Patients with VSP showed a wider upper motor neuron impairment, whereas the involvement of LMN resulted greater in patients with HSP. Patients with HSP exhibited a greater drop of ALSFRS-r sub-score in the region of onset, while VSP showed a slighter but more diffuse reduction of ASLFRS-r subscore in more body districts beyond the site of onset. Patients with VSP were also characterized by a higher median progression rate and an earlier median bulbar involvement, compared to HSP. CONCLUSIONS: Our findings suggested investigating the spreading direction of ALS among patients with spinal onset, to better delineate the clinical profiles of patients with ALS, and predict an earlier impairment of bulbar muscle and a more rapid progression of the disease.

Split-elbow sign in the PRO-ACT and Southern Italy ALS cohorts: a potential marker of disease severity and lower motor neuron involvement?

INTRODUCTION: Split phenomena in ALS refers to the preferential dysfunction of some groups of muscles over others. The split-elbow sign (SE) is characterized by the predominant weakness of the biceps compared to the triceps, but available results are conflicting. OBJECTIVES: To evaluate the prevalence of the SE in two independent cohorts: the randomized controlled trial-based PRO-ACT cohort (n = 500) and a monocentric cohort of patients with ALS from Southern Italy (n = 144); to investigate the demographic and clinical variables associated with the SE sign. METHODS: Wilcoxon signed-rank test was used to compare biceps with triceps power in the same limb measured by hand-held dynamometry in the PRO-ACT cohort and Medical Research Council (MRC) in our cohort. Each limb was considered independently and not paired within the same individual. The arm where the triceps was stronger than the biceps was defined SE + , whereas the arm where the biceps was stronger than the triceps was considered SE-. A backward stepwise multivariate logistic regression was used to analyze the relationship between clinical and demographic variables and SE. PENN Upper Motor Neuron and Devine scales were used to evaluate the different upper (UMN) and lower (LMN) motor neuron impairments between the SE + and SE- arms. RESULTS: In both cohorts, the biceps were on average stronger than the triceps, and the SE sign was present in 41% of the PRO-ACT cohort and just 30% of the Southern Italy cohort. The multivariate logistic regression revealed that older age (OR: 1.45; p = 0.01), male gender (OR: 1.55; p = 0.002), spinal onset (OR: 1.59; p = 0.007), and higher disease severity (OR: 1.70; p = 0.001) were significant predictors of the SE sign in the PRO-ACT cohort. Conversely, in Southern Italy patients, only a lower ALSFRS-R score was a significant determinant of the SE (OR: 8.47; p = 0.008). Finally, SE + arms exhibited a significantly higher median Devine sub-score compared to SE- [1 vs 0, p = < 0.05], while arms SE- showed a significantly higher median PUMNS sub-score [2 vs 0; p = < 0.05)]. CONCLUSION: In our study, most patients with ALS do not show SE. Patients with SE are more likely older, males, with spinal onset, a higher degree of disease severity, and predominant and wider LMN impairment.

AChR+ Ocular Myasthenia and Facial Hemispasm: A Case Report of Unusual Association and Botulinum Toxic Type A Safety and Efficacy.

INTRODUCTION: Hemifacial spasm represents segmental myoclonus of muscles innervated by the facial nerve, which is usually and successfully treated with botulinum toxin. Botulinum toxin (BTX) acts as an acetylcholine release inhibitor at presynaptic cholinergic junctions and therefore is considered contraindicated (or administrable with caution) in patients with neuromuscular disorders like Myasthenia Gravis (MG). Moreover, to date, the association of hemifacial spasm and ocular MG is extremely rare and only a few cases have been described. CASE PRESENTATION: We report the case of a 73 years old man with a 3-year history of ocular MG who developed a left hemifacial spasm. The patient underwent hemispasm, treatment with BTX type A (abobotulinum toxin-A, total dose of 50 IU) that resulted in safe and successful 6 months re-evaluation. CONCLUSION: Our results suggest that in selected cases with concomitant MG and conditions characterized by orbicularis oculi spasms or hemispasm, BTX therapy may not be contraindicated and could be given at longer intervals due to prolonged effects.

Amyotrophic Lateral Sclerosis-The Complex Phenotype-From an Epidemiological Perspective: A Focus on Extrapyramidal and Non-Motor Features.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease (MND) and has emerged, among the disorders, with the largest increase in incidence in Western countries. Although the typical clinical phenotype of ALS involves simultaneous upper and lower motor neurons, there is growing evidence that the neurodegeneration during the course of the disease can also involve other motor and non-motor regions. In this review, we analyzed and discussed available data from epidemiological population-based studies on extrapyramidal and non-motor features during the course of ALS.

Split phenomena in amyotrophic lateral sclerosis: Current evidences, pathogenetic hypotheses and diagnostic implications.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease and has emerged among the disorders with the largest increasing incidence in Western countries. Although the diagnosis is based on clinical grounds, electromyography (EMG), and nerve conduction studies (NCS) play a crucial role to exclude other potential etiologies of lower motor neuron (LMN) dysfunction. Based on clinical grounds, a peculiar pattern of dissociated atrophy of the intrinsic hand and foot muscles, termed the "split-hand" (SH) and "split-leg" (SL) signs, has been described in a significant proportion of subjects with ALS, even at the early stages of the disease, when symptoms are focal. These signs are rare in neurological and non-neurological diseases other than ALS. In this review, we discussed current evidences concerning SH and SL signs, their pathogenetic hypotheses and neurophysiological findings. We also analyze whether SH and SL signs can be reliable markers in the differential diagnosis and in the prognosis of ALS.

King's college progression rate at first clinical evaluation: A new measure of disease progression in amyotrophic lateral sclerosis.

BACKGROUND: To estimate King's college clinical stage progression rate (ΔKC) at first clinical evaluation in order to define its predictive and prognostic role on survival in a large cohort of Amyotrophic Lateral Sclerosis (ALS) patients. METHODS: The ΔKC was calculated with the following formula: 0 - KC clinical stage at first clinical evaluation/disease duration from onset to first evaluation, and each result was reported as absolute value. All the evaluations were performed in two cohorts: one from our tertiary centre for motor neuron disease and the other one from a pooled resource open-access ALS clinical trials (PRO-ACT) database. C-statistic was used to evaluate the model discrimination of survival at different time points (1-3 years). Cox proportional hazard model was used to identify factors associated with survival. RESULTS: ΔKC predicted survival at three years in our centre and in the PRO-ACT cohort (C-statistic 0.83, 95% CI 0.8-0.86, p < 0.0001; 0.7, 95% CI 0.68-0.73, p < 0.0001, respectively). At multivariate analysis, ΔKC was independently associated with survival both in our cohort (HR 3.62 95% CI 2.71-4.83 p = 0.001) and in the PRO-ACT cohort (HR 2.75 95% CI 2.1-3.6 p = 0.001). CONCLUSIONS: Based on our results, ΔKC could be used as a novel measure of disease progression, hence as an accurate predictor of survival in ALS patients. Indeed, greater values of ΔKC were associated with a 3.5-fold higher risk to experience the event, confirming its robust prognostic value.

Reduction of Sniff Nasal Inspiratory Pressure (SNIP) as an Early Indicator of the Need of Enteral Nutrition in Patients with Amyotrophic Lateral Sclerosis.

Percutaneous endoscopic gastrostomy (PEG) is the standard procedure for feeding severely dysphagic patients with amyotrophic lateral sclerosis (ALS). It is associated with prolonged survival and improvement in quality of life. Nasal inspiratory pressure during a sniff (SNIP) is a respiratory test used extensively in ALS for the assessment of inspiratory muscle strength. In this study, we aimed to investigate the role of SNIP at baseline to predict PEG placement in ALS. Data from a clinical incident cohort of 179 ALS cases attending the multidisciplinary ALS unit of the University of Bari between April 2006 and December 2012 were retrospectively analysed. At baseline, patients underwent detailed neurological, nutritional and respiratory assessments, including measurements of SNIP and forced vital capacity (FVC). Patients were therefore followed up approximately every three to six months until they were able to attend the centre. The censoring date for the survival analysis was 15 April 2014, with PEG placement as the main outcome. Cox proportional hazard regression models were used to examine the association between SNIP and PEG placement, adjusted for possible confounders. During the follow-up period, 75 participants (42%) received PEG implant. PEG placement was more frequent (57% vs. 31%; p = 0.001) and earlier (after 11.6 ± 14.0 months from the first visit, vs. 23.3 ± 15.5 months; p < 0.0001) in the group of patients with baseline SNIP ≤ 40 cm H2O. Baseline SNIP was a predictor of PEG placement even after correction for multiple potential confounders (HR 0.98; 95% CI: 0.96-0.99; p = 0.02). To conclude, the present study showed that SNIP at baseline is an early indicator of disease progression and therefore of the need for enteral nutrition in ALS.

Subclinical upper motor neuron involvement at the diagnosis may predict disease progression in a cohort of lower motor neuron syndromes from Southern Italy.

BACKGROUND: Only few epidemiological studies on survival of Lower Motor Neuron (LMN) phenotype (LMNP) are available and with controversial results. AIMS: To prospectively evaluate a cohort of LMNP patients and assess the possible contribute on survival or disease's progression according to the presence of subclinical Upper Motor Neuron (UMN) impairment at the diagnosis. METHODS: Forty LMNP among 176 consecutive incident ALS cases observed in our tertiary center from the ALS-Apulia Register were enrolled in the study. Each patient underwent to a neurophysiological study with transcranial magnetic stimulation (TMS) at diagnosis. The primary outcome was the impact of abnormalities at TMS on survival time (from symptoms onset or diagnosis to death, tracheostomy or 30 June 2020, as censoring time). Secondary outcome was time to reach the King's 4 stage. RESULTS: Approximately one half of LMNP reached the primary outcome during the study period. No difference was found in median survival times and 4 years survival rates according to the presence of TMS impairment. On the other hand, a shorter median time to reach the King's 4 from onset was observed in the group of LMNP with TMS abnormalities (16 months versus 50 months; p = 0.008). Consistently, TMS abnormalities were associated with a 3.5 times higher risk for reaching King's 4 stage (Hazard Ratio: 3.5; 95% Confidence Interval: 1.1-10.9; p = 0.03). CONCLUSION: Our data suggest a role of TMS abnormalities as potential indicator of disease progression and multidistrectual involvement in patients with pure clinical LMN phenotype at the diagnosis.